The Human Cytomegalovirus U<sub>L</sub>26 Protein Antagonizes NF-κB Activation

Mathers, Chun; Schafer, Xenia; Martínez-Sobrido, Luis; Munger, Joshua

doi:10.1128/jvi.02552-14

Cited by 51 publications

(82 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When IκB is phosphorylated by an upstream kinase complex, NF‐κB was degraded via the ubiquitin‐proteasome pathway. Activated NF‐κB is translocated into the nucleus and then binds to promoter regions for target gene expression . The NF‐κB family of transcription factors includes the critical regulators of proinflammatory and antiapoptotic gene transcription programs .…”

Section: Introductionsupporting

confidence: 86%

“…Activated NF-B is translocated into the nucleus and then binds to promoter regions for target gene expression. [14] The NF-B family of transcription factors includes the critical regulators of proinflammatory and antiapoptotic gene transcription programs. [15] Sandur et al [16] showed that transient inducible NF-B activation causes a prosurvival response to radiation in rectal cancers, which may be responsible for development of radioresistance.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway

Zhang

et al. 2017

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Sulforaphene (SFE), a naturally occurring isothiocyanate found in cruciferous vegetables, has attracted increasing attention for its anti-cancer effect in many cancers, including hepatocellular carcinoma (HCC). However, the precise role of SFE in the radiosensitivity of HCC is still unclear. Here, cell proliferation and apoptosis were detected by MTT and flow cytometry assay, respectively. The activity of NF-κB was further evaluated by ELISA. We also observed the effect of SFE and/or radiation on tumor growth. The results showed that SFE inhibited cell proliferation and induced apoptosis in HCC cells. Radiation increased NF-kB activity, while PDTC, a NF-kB inhibitor, enhanced radiation-induced cell death. SFE inhibited NF-kB activity and the downstream gene expressions of the NF-kB pathway in HCC cells. Moreover, SFE enhanced the inhibitory effect of radiation on tumor growth both in vitro and in vivo. This study indicated that SFE sensitized the radiosensitivity of HCC by blocking the NF-kB pathway.

show abstract

Section: Introductionsupporting

confidence: 86%

mentioning

confidence: 99%

Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway

Zhang

et al. 2017

J Biochem & Molecular Tox

View full text Add to dashboard Cite

show abstract

“…Recently, UL26, an early protein, was found to inhibit NF-κB activation by attenuating IKK phosphorylation in TNFα-treated cells [24]. The results of the present study reveal that UL48 and UL45, expressed at delayed-early or late times after infection, are potent suppressors of NF-κB activation in the late stages of infection.…”

Section: Discussionsupporting

confidence: 57%

Cooperative inhibition of RIP1-mediated NF-κB signaling by cytomegalovirus-encoded deubiquitinase and inactive homolog of cellular ribonucleotide reductase large subunit

Kwon

Kim

et al. 2017

PLoS Pathog

View full text Add to dashboard Cite

Several viruses have been found to encode a deubiquitinating protease (DUB). These viral DUBs are proposed to play a role in regulating innate immune or inflammatory signaling. In human cytomegalovirus (HCMV), the largest tegument protein encoded by UL48 contains DUB activity, but its cellular targets are not known. Here, we show that UL48 and UL45, an HCMV-encoded inactive homolog of cellular ribonucleotide reductase (RNR) large subunit (R1), target receptor-interacting protein kinase 1 (RIP1) to inhibit NF-κB signaling. Transfection assays showed that UL48 and UL45, which binds to UL48, interact with RIP1 and that UL48 DUB activity and UL45 cooperatively suppress RIP1-mediated NF-κB activation. The growth of UL45-null mutant virus was slightly impaired with showing reduced accumulation of viral late proteins. Analysis of a recombinant virus expressing HA-UL45 showed that UL45 interacts with both UL48 and RIP1 during virus infection. Infection with the mutant viruses also revealed that UL48 DUB activity and UL45 inhibit TNFα-induced NF-κB activation at late times of infection. UL48 cleaved both K48- and K63-linked polyubiquitin chains of RIP1. Although UL45 alone did not affect RIP1 ubiquitination, it could enhance the UL48 activity to cleave RIP1 polyubiquitin chains. Consistently, UL45-null virus infection showed higher ubiquitination level of endogenous RIP1 than HA-UL45 virus infection at late times. Moreover, UL45 promoted the UL48-RIP1 interaction and re-localization of RIP1 to the UL48-containing virion assembly complex. The mouse cytomegalovirus (MCMV)-encoded DUB, M48, interacted with mouse RIP1 and M45, an MCMV homolog of UL45. Collectively, our data demonstrate that cytomegalovirus-encoded DUB and inactive R1 homolog target RIP1 and cooperatively inhibit RIP1-mediated NF-κB signaling at the late stages of HCMV infection.

show abstract

“…Most of these ISG15 binding and all of UBE1L binding in yeast assays were also detected by co-immunoprecipitation (co-IP) assays (S4 Fig and S2 Table). Among them, the UL26 gene encodes the tegument proteins, p27 and p21, which are produced using two in-frame start codons and are shown to regulate viral gene expression, NF-κB signaling, and virion stability [71][72][73][74]. Since UL26 interacted with both ISG15 and UBE1L and its role in viral growth was relatively well reported compared to others, we further investigated the interaction of pUL26 with the ISG15 pathway.…”

Section: Covalent and Non-covalent Interaction Of Pul26 With Isg15mentioning

confidence: 99%

Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators

Kim

et al. 2016

PLoS Pathog

View full text Add to dashboard Cite

Interferon-stimulated gene 15 (ISG15) encodes an ubiquitin-like protein that covalently conjugates protein. Protein modification by ISG15 (ISGylation) is known to inhibit the replication of many viruses. However, studies on the viral targets and viral strategies to regulate ISGylation-mediated antiviral responses are limited. In this study, we show that human cytomegalovirus (HCMV) replication is inhibited by ISGylation, but the virus has evolved multiple countermeasures. HCMV-induced ISG15 expression was mitigated by IE1, a viral inhibitor of interferon signaling, however, ISGylation was still strongly upregulated during virus infection. RNA interference of UBE1L (E1), UbcH8 (E2), Herc5 (E3), and UBP43 (ISG15 protease) revealed that ISGylation inhibits HCMV growth by downregulating viral gene expression and virion release in a manner that is more prominent at low multiplicity of infection. A viral regulator pUL26 was found to interact with ISG15, UBE1L, and Herc5, and be ISGylated. ISGylation of pUL26 regulated its stability and inhibited its activities to suppress NF-κB signaling and complement the growth of UL26-null mutant virus. Moreover, pUL26 reciprocally suppressed virus-induced ISGylation independent of its own ISGylation. Consistently, ISGylation was more pronounced in infections with the UL26-deleted mutant virus, whose growth was more sensitive to IFNβ treatment than that of the wild-type virus. Therefore, pUL26 is a viral ISG15 target that also counteracts ISGylation. Our results demonstrate that ISGylation inhibits HCMV growth at multiple steps and that HCMV has evolved countermeasures to suppress ISG15 transcription and protein ISGylation, highlighting the importance of the interplay between virus and ISGylation in productive viral infection.

show abstract

The Human Cytomegalovirus U_L26 Protein Antagonizes NF-κB Activation

Cited by 51 publications

References 59 publications

Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway

Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway

Cooperative inhibition of RIP1-mediated NF-κB signaling by cytomegalovirus-encoded deubiquitinase and inactive homolog of cellular ribonucleotide reductase large subunit

Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators

Contact Info

Product

Resources

About

The Human Cytomegalovirus UL26 Protein Antagonizes NF-κB Activation

Cited by 51 publications

References 59 publications

Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway

Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway

Cooperative inhibition of RIP1-mediated NF-κB signaling by cytomegalovirus-encoded deubiquitinase and inactive homolog of cellular ribonucleotide reductase large subunit

Consecutive Inhibition of ISG15 Expression and ISGylation by Cytomegalovirus Regulators

Contact Info

Product

Resources

About

The Human Cytomegalovirus U_L26 Protein Antagonizes NF-κB Activation